Methods for enhancing the release and absorption of water insoluble active agents

ABSTRACT

Methods for enhancing the release and/or absorption of poorly water soluble active agents are described herein. The method involves dissolving, melting, or suspending a poorly water soluble active agent in one or more molten fatty acids, conjugated fatty acids, (semi-) solid surfactants of high HLB value, and/or hydrophilic polymers. The molten active agent mixture is then suspended and homogenized in a hydrophilic or lipophilic carrier to form microparticles suspended in the hydrophilic or lipophilic carrier. The particles suspended in the hydrophilic or lipophilic carrier can be encapsulated in a hard or soft gelatin or non-gelatin capsule. It is believed that the microparticles produced by the method described above will exhibit enhanced dissolution profiles. In vitro release studies of formulations containing cilostazol and fenofibrate showed 100% dissolution of cilostazol in 15 minutes and over 90% dissolution of fenofibrate in 35 minutes.

CROSS REFERENCE TO RELATED APPLICATIONS

The application claims priority to U.S.S.N, 61/122,497 entitled “Methodsfor Enhancing the In Vitro Release and Absorption of Water InsolubleActive Agents” by Aqeel Fatmi, Tae Kyoung Kim, and Karla Madrigal, filedDec. 15, 2008.

FIELD OF THE INVENTION

This invention is generally in the field of methods of manufacture ofmicroparticles with enhanced release and absorption of water-insolubleactive agents.

BACKGROUND OF THE INVENTION

Formulation of poorly water soluble active agents, particularly inliquid and semi-solid forms, is a challenging task due toincompatibility between the carrier and the fill material. Thisincompatibility can result in agglomerization of the active agent overtime which can result in low in vitro/in vivo dissolution. Further,active agents which have low solubility in water and/or low absorptionin vivo (classified as BCS Class II and Class IV active agents under theBiopharmaceutical Classification System) can be difficult to integrateinto a formulation due to the uncertainty surrounding the correlationbetween in vitro and in vivo performance. For example, BCS Class II andClass IV active agents can exhibit significant food effects,particularly with high fat meals.

Different techniques for enhancing the solubility and bioavailability ofwater soluble active agents have been described in the literature. U.S.Pat. No. 5,145,684 to Liversidge et al. describes dispersible particlescontaining a crystalline active agent substance having a surfacemodifier absorbed on the surface thereof. The particles are made by wetmilling in the presence of grinding media in conjunction with a surfacemodifier. Liversidge does not disclose or suggest making microparticlesby melting or dissolving a water-insoluble active agent in a coatingmaterial and adding the mixture to a hydrophilic or lipophilic carrierto form microparticles.

U.S. Pat. No. 6,652,881 to Stamm et al. describes compositionscontaining micronized fenofibrate, wherein the compositions have adissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20minutes, and 75% in 30 minutes as measured using the rotating blade at75 rpm according to the European Pharmacopoeia, in a dissolution mediumconstituted by water with 2% by weight polysorbate 80 or 0.025 M sodiumlauryl sulfate. The compositions contain an inert hydrosoluble carriercovered with at least one layer containing a fenofibrate activeingredient in a micronized form, a hydrophilic polymer, and optionally asurfactant; and optionally one or several outer phase(s) or layer(s).Stamm does not disclose or suggest making microparticles by melting ordissolving a water-insoluble active agent in a coating material andadding the mixture to a hydrophilic or lipophilic carrier to formmicroparticles.

U.S. Pat. No. 6,375,986 to Ryde et al. describes solid dosenanoparticulate compositions comprising a poorly soluble active agent,at least one polymeric surface stabilizer, and dioctyl sodiumsulfosuccinate (DOSS). The polymeric surface stabilizer is adsorbed onthe surface of the active agent in an amount sufficient to maintain aneffective average particle size of less than about 1 micron. Ryde doesnot disclose or suggest making microparticles by melting or dissolving awater-insoluble active agent in a coating material and adding themixture to a hydrophilic or lipophilic carrier to form microparticles.

U.S. Pat. No. 5,545,628 to Deboeck et al. describes a pharmaceuticalcomposition for treating hyperlipidemia or hypercholesterolemia or bothin a mammal, which contains an effective amount of each of fenofibrateand an excipient containing one or more polyglycolyzed glycerides. Thecompositions are prepared by co-melting the fenofibrate and thepolyglycolyzed glycerides to form a homogeneous mixture or solution. Themolten mixture can be filled into hard gelatin capsules. Deboeck doesnot disclose or suggest making microparticles by melting or dissolving awater-insoluble active agent in a coating material and adding themixture to a hydrophilic or lipophilic carrier to form microparticles.

WO 2006/062933 to Reliant Pharmaceuticals, Inc. describes fenofibratecompositions containing fenofibrate solubilized in fatty acid esters.The acid portion or the ester portion of the fatty acid is a C₁-C₁₅group, preferably a C₁-C₆, more preferably a C₁-C₄ group. Thefenofibrate may be dissolved in the fatty acid esters with or withoutthe use of heat, preferably without heating. The '933 application doesnot disclose or suggest making microparticles by melting or dissolving awater-insoluble active agent in a coating material and adding themixture to a hydrophilic or lipophilic carrier to form microparticles.

There exists a need for additional methods for enhancing the solubilityand bioavailability of water-insoluble active agents.

Therefore, it is an object of the invention to provide methods forenhancing the solubility and bioavailability of water-insoluble activeagents.

It is further an object of the invention to provide compositions whichexhibit enhanced solubility and bioavailability of water-insolubleactive agents and methods of using thereof.

SUMMARY OF THE INVENTION

Methods for enhancing the in vivo release and absorption of poorly watersoluble active agents are described herein. The method involvesdissolving, melting, or suspending a poorly water soluble active agentin one or more fatty acids, conjugated fatty acids, (semi-) solidsurfactants having a high HLB value, and/or hydrophilic polymers.Suitable fatty acids include C₁₀-C₁₈ fatty acids, preferably C₁₆-C₁₈fatty acids. Suitable conjugated fatty acids include C₁₀-C₁₈ fattyacids, preferably C₁₆-C₁₈ fatty acids, conjugated with glycerol (e.g.,monoglycerides), monosaccharides, and/or polyethylene glycol (PEG).Suitable hydrophilic polymers include poloxomers and poloxamines.

The active agent mixture is suspended and homogenized in a hydrophilicor lipophilic phase to form microparticles suspended in the hydrophilicor lipophilic phase. The hydrophilic or lipophilic phase can act as asecondary rate controlling barrier which modifies the rate of release ofthe active agent. The particles suspended in the hydrophilic orlipophilic phase can be formulated in an oral dosage form. For example,the microparticles dispersed in the hydrophilic or lipophilic carriercan be encapsulated in a hard or soft gelatin or non-gelatin capsule.

The particle size of the final formulation is determined by thehomogenization process, particularly the homogenization time. Typicalparticles sizes are between 50 nm and 25 microns. In one embodiment, thediameter of the particles is from about 0.1 to about 25 microns,preferably from about 10 to about 25 microns, more preferably from about10 to about 20 microns. In another embodiment, the microparticles have adiameter less than 10 microns, less than 5 microns, less than 1 micron,less than 0.5 microns, less than 0.25 microns, or less than 0.1 micron.The microparticles may be spherical or any other shape.

The microparticles produced by the method described herein can exhibitenhanced dissolution profiles. In vitro release studies of formulationscontaining cilostazol and fenofibrate showed 100% dissolution ofcilostazol in 15 minutes and over 90% dissolution of fenofibrate in 35minutes. Further, fatty acid-coated cilostazol nanoparticles exhibitedenhanced absorption in vivo compared to Pletal® (cilostazol in tabletform, suspended in water) and cilostazol suspended in an oil-basedcarrier containing lecithin and Capmul (CLZ-02).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph showing the dissolution profile in vitro formicroparticles containing fenofibrate (% fenofibrate released) and afatty acid (polyoxyl 40 stearate (□) and glyceryl monostearate, (∘))suspended in polyethylene glycol (PEG) as a function of time (minutes)compared to fenofibrate and fatty acid suspended in polyoxyl 40 stearateand glyceryl monostearate (⋄). FIG. 1B is a graph showing thedissolution profile in vitro for microparticles containing cilostazol (%cilostazol released) and a fatty acid conjugate (glyceryl ester ofbehenate, sold as Compritol 888 ATO and available from Gattfosse,Saint-Priest, France) (⋄) coated with polyoxyl 40 stearate as a functionof time (minutes) with (□) and without (Δ) homogenization compared tocilostazol suspensions in lecithin and Capmul.

FIG. 2A is a graph showing the enhanced absorption in vivo under fastingconditions for glycerin ester of behenate-coated cilostazolnanoparticles compared to Pletal® (cilostazol in tablet form, suspendedin water) and cilostazol suspended in an oil-based carrier containinglecithin and Capmul (CLZ-02). FIG. 2B is a graph showing the enhancedabsorption in vivo under fed conditions for glycerin ester ofbehenate-coated cilostazol nanoparticles versus Pletal® (cilostazol intablet form) and CLZ-02.

FIG. 3A is a graph showing the difference in absorption of fenofibrate(fenofibric acid, ng/mL) as a function of time (hours) for fattyacid-coated fenofibrate (∘) and fenofibrate suspended in water (Δ) underfasting conditions. FIG. 3B is a graph showing the difference inabsorption of fenofibrate (fenofibric acid, ng/mL) as a function of time(hours) for fatty acid-coated fenofibrate (♦) and fenofibrate suspendedin water (▴) under non-fasting conditions and fatty acid-coatedfenofibrate taken after a high fat meal (*).

FIG. 4 is a graph showing the food effect on the absorption of threefenofibrate formulations: a reference formulation (described in Example3); solid lipid nanoparticles (SLN); and solid lipid nanoparticles withhigh fat (SLN HF), as a function of the formulation.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

“Water-insoluble active agent”, as used herein, refers to an activeagent which does not dissolve in water and/or does not form a homogenoussingle phase with water. For example, the active agent may have asolubility in water less than 10 mg/ml at 25° C., less than 5 mg/ml at25° C., less than 1 mg/ml at 25° C., or less than 0.5 mg/ml at 25° C.

“Lipophilic carrier”, as used herein, refers to a material or materialsthat have an affinity for lipids.

“Hydrophilic carrier”, as used herein, refers to a material or materialshaving an affinity for water.

“Semi-solid”, as used herein, refers to a material or materials havingthe attributes of both a solid and a liquid, for example, having therigidity and viscosity intermediate between a solid and a liquid.

“Microparticles”, as used herein, generally refers to a particle of arelatively small size, but not necessarily in the micron size range; theterm is used in reference to particles of sizes that can be, forexample, less than about 50 nm to about 100 microns or greater. In oneembodiment, the diameter of the particles is from about 0.1 to about 25microns, preferably from about 10 to about 25 microns, more preferablyfrom about 10 to about 20 microns. In another embodiment, the diameterof the particles is less than 10 microns, less than 5 microns, less than1 micron, less than 0.5 microns, less than 0.25, or less than 0.1microns. As used herein, the term microparticle encompassesmicrospheres, microcapsules, microparticles, and nanoparticles unlessspecified otherwise. The microparticle may be of composite constructionand is not necessarily a pure substance. The microparticles may bespherical or any other shape.

“Poor absorption”, as used herein, refers to a drug which has limitedabsorption in the gastrointestinal tract. Drugs having poor absorptionin the gastrointestinal tract generally have low aqueous solubility,e.g., less than 10 mg/ml at 25° C.

“High permeability”, as used herein, refers to drugs wherein the extentof absorption in humans is determined to be >90% of an administereddose, based on mass-balance or in comparison to an intravenous referencedose.

“High hydrophile-lipophile balance” or “high HLB”, as used herein,generally refers to a material or materials having an HLB of greaterthan about 10, preferably greater than 16.

“Surfactant”, as used herein, refers to amphiphilic compounds, that is,compounds containing both hydrophilic and hydrophobic groups.Surfactants can be classified by their hydrophile-lipophile balance(HLB). Surfactants with lower HLB value are more lipophilic, whilesurfactants with a higher HLB value are more hydrophilic.

“AUC₀₋₂₄”, as used herein, refers to the area under the plasmaconcentration curve from time zero to 24 hours. The AUC₀₋₂₄ iscalculated using the linear trapezoidal rule.

II. Methods of Making Microparticles

Methods of making microparticles containing one or more water-insolubleactive agents are described herein. The microparticles contain theactive agent coated with, dissolved in, or dispersed in one or morecoating materials. Exemplary coating materials include fatty acids,conjugated fatty acids, surfactants having a high HLB, hydrophilicpolymers, and combinations thereof. The microparticles can exhibitrelatively rapid dissolution and enhanced absorption of the active agentcompared to the active agents suspended in an aqueous or oil-basedcarrier.

A. Active Agents

Any therapeutic, prophylactic, or diagnostic agent, nutraceutical, orother agent (collectively referred to as “active agents”) can beincorporated into the microparticles. The active agent typically has alow solubility in water and/or poor absorption in vivo. In oneembodiment, the active agent is an active agent having high permeabilityand low solubility in vivo or an active agent having low permeabilityand low solubility in vivo. Under the Biopharmaceutics ClassificationSystem, such active agents are characterized as Class II and IV activeagents, respectively.

Suitable classes of active agents include, but are not limited to,analgesics, anti-inflammatory agents, antihelmintics, anti-arrhythmicagents, antibacterials, anticoagulants, antidepressants, antidiabetics,antiepileptics, antimalarials, antimigrane agents, antihistamines,antihypertensives, antimuscarinic agents, antimycobacterial agents,antineoplastic agents, immunosuppressants agents, antiprotozoal agents,antithyroid agents, antiviral agents, anxiolytic sedatives, astringents,beta adrenoceptor blocking agent, blood products and substitutes,cardiac ionotropic agents, corticosteroids, cough suppressants,diagnostic agents, diuretics, dopaminergics, haemostatics, lipidregulating agents, muscle relaxants, parasympathomimetics,prostaglandins, sex hormones, stimulants and anoretics,sympathomimetics, thyroid agents, and vasodilators.

Examples of Class II and Class IV active agents are described in Amidonet al., Mol. Pharm., Vol. 1, No. 1, 85-96 (2004)). Examples of Class IIand Class IV active agents include, but are not limited to, fenofibrate,cilostazol, acetazolamide, albendazole, allopurinol, azothioprine,carbamazepine, clofazimine, dapsone, diazepam, diloxanide furoate,doxycycline, efavirenz, furosemide, glibenclamide, griseofulvin,haloperidol, ibuprofen, lopinavir, nevirapine, niclosamide, nifedipine,paracetamol, parathyroid calcitonin, retinal palmitate, ritonavir,sulfadiazine, sulfamethoxazole, and sulfasalazine.

The concentration range of the active agent is up to about 50%,preferably about 1 to about 30%, more preferably from about 1 to about15% by weight of the composition containing the microparticles andcarrier. Alternatively, the percent loading of the drug in themicroparticles is from about 1% to about 50%, from about 1% to about40%, from about 1% to about 30%, from about 1% to about 25%, or fromabout 1% to about 20%.

In one embodiment, the active agent is a fibrate, such as fenofibrate.As used herein the term “fibrate” means any of the fibric acidderivatives useful in the methods described herein, e.g., fenofibrate.Fenofibrate is a fibrate compound, other examples of which arebezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate,clofibrate, clofibric acid, etofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, and theofibrate.

Generally, fibrates are used to treat conditions such ashypercholesterolemia, mixed lipidemia, hypertriglyceridemia, coronaryheart disease, and peripheral vascular disease (including symptomaticcarotid artery disease), and prevention of pancreatitis. Fenofibrate mayalso help prevent the development of pancreatitis (inflammation of thepancreas) caused by high levels of triglycerides in the blood. Fibratesare also known to be useful in treating renal failure. Fibrates may alsobe used for other indications where lipid regulating agents aretypically used.

As used herein the term “fenofibrate” is used to mean fenofibrate(2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester) or a salt thereof. Fenofibrate is used to lower triglyceride(fat-like substances) levels in the blood. Specifically, fenofibratereduces elevated LDL-C, Total-C, triglycerides, and Apo-B and increasesHDL-C. The drug has also been approved as adjunctive therapy for thetreatment of hypertriglyceridemia, a disorder characterized by elevatedlevels of very low density lipoprotein (VLDL) in the plasma.

The absolute bioavailability of conventional microcrystallinefenofibrate cannot be determined as the compound is virtually insolublein aqueous media suitable for injection. However, fenofibrate is wellabsorbed from the gastrointestinal tract.

In another embodiment, the active agent is cilastazol. Cilostazol is aselective PDE3 phosphodiesterase inhibitor with therapeutic focus oncAMP. It inhibits platelet aggregation and is a direct arterialvasodilator. Its main effects are dilation of the arteries supplyingblood to the legs and decreasing platelet coagulation.

B. Coating Materials

The water-insoluble active agent is coated with one or more coatingmaterials. Exemplary coating materials include fatty acids, conjugatedfatty acids, surfactants having a high HLB, hydrophilic polymers, andcombinations thereof. The coating materials are preferably notphospholipids.

1. Fatty Acids and Esters of Fatty Acids

Suitable fatty acids include C₁₀-C₁₈ fatty acids, more preferablyC₁₆-C₁₈ fatty acids. Exemplary fatty acids include, but are not limitedto, dodecanoic (lauric) acid, tetradecanoic (myristic) acid,hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid,octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic(behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic)acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid,triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid,tritriacontanoic (ceromelissic) acid, tetratriacontanoic (geddic) acid,and pentatriacontanoic (ceroplastic) acid. The fatty acids can besaturated fatty acids, monounsaturated fatty acids, polyunsaturatedfatty acid, or combinations thereof.

Oils, for example, vegetable oils, such as soybean oil can be used aloneor in combination with the coating materials listed above. Soybean oilcontains 14.4% saturated fatty acids, 23.3% monounsaturated fatty acids,such as oleic acid, and 57.9% polyunsaturated fatty acids, such aslinoleic acid and alpha linoleic acid.

In one embodiment, the fatty acid is covalently coupled to glycerol, amonosaccharide, such as sorbitol or sorbitan, a polyalkylene oxide, suchas polyethylene glycol and polypropylene glycol, or combinationsthereof. These materials are referred to as conjugated fatty acids.Suitable conjugated fatty acids include, but are not limited to,polyethylene glycol esters of fatty acids, such as those availablecommercially under the tradename Gelucire®, sorbitan esters of fattyacids, such as sorbitan monostearate, glycerol fatty acid esters of thefatty acids listed above, such as glycerol behenate and glycerylmonostearate, and combinations thereof.

The concentration range of the fatty acid is from about 1 to about 20%by weight of the composition, preferably from about 5 to about 15% byweight of the composition (microparticles and carrier).

2. Surfactants Having High HLB

The water-insoluble active agent can be coated with one or moresurfactants, alone or in combination with or more fatty acids orconjugated fatty acids and/or one or more hydrophilic polymers. In oneembodiment, the surfactant has an HLB value greater than about 10,greater than about 12, greater than about 14, or greater than about 16(on a scale of 1-18). Surfactants having the desired HLB are known inthe art. The surfactant can be anionic, cationic, or non-ionic. In oneembodiment, the surfactant is a non-ionic surfactant.

Examples of such surfactants include, but are not limited to,polysorbate 20, 40, and 80 (marketed under the name TWEEN®),polyoxyethylene monostearate, some sugar esters, such as sucrosemonolaurate, ethoxylated nonyl phenols, alpha olefin sulfonates,ethoxylated tallow amines, ethylene oxide/propylene oxide blockcopolymers, ethoxylated soya amines, fatty acids and alcohols,polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers,and polyoxyethylene stearates.

In one embodiment, the surfactant is a high HLB surfactant containing afatty acid chain. Suitable surfactants include, but are not limited to,polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers,and polyoxyethylene stearates.

Polyoxyethylene castor oil derivatives contain mainly ricinoleylglycerol ethoxylated with 30-50 molecules of ethylene oxide.Polysorbates or polyoxyethylene sorbitan fatty acid esters are a seriesof partial fatty acids esters of sorbitol and its anhydridescopolymerized with approximately 20, 5, or 4 moles of ethylene oxide foreach mole of sorbitol and its anhydrides. The resulting product is amixture of molecules having a wide range of molecular weights.Polyoxyethylene alkyl ethers are a series of polyoxyethylene glycolethers of linear fatty alcohols (n-alcohols), such as lauryl, myristyl,cetyl, and stearyl alcohol. Polyoxyethylene stearates are produced bypolyethoxylation of stearic acid.

Without desiring to be bound by any theory, it is believed that thehydrophilic part of the surfactant enhances the compatibility of theactive agent with the aqueous dissolution media in vitro or in vivo andthat the fatty acid side chain enhances absorption via fatty acidoxidation. During fatty acid oxidation, intracellular Ca²⁺ is consumedwhich results in the widening of gap junctions, allowing passage of theactive agent between cells. Further, such coated particles may be morestable than drug alone, for example, by preventing oxidation of theactive agent.

The concentration of the surfactant is from about 1 to about 50%,preferably from about 5 to about 15% by weight of the composition(microparticles and carrier).

3. Hydrophilic Polymers

Suitable hydrophilic polymers include, but are not limited to,poloxamers, poloxamines, polyethylene glycols, polyvinyl alcohols,polyvinylpyrrolidone, poly(vinyl alcohol), cellulosic materials, such ashydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethyl-cellulose, gelatin, carboxymethyl cellulose, andpolypeptides.

The concentration of the hydrophilic polymer is from about 1 to about50% by weight of the composition, more preferably from about 5 to about15% by weight of the composition. If the hydrophilic polymer is apolyethylene glycol, the concentration is from about 1 to about 80% byweight of the composition, from about 30 to about 60%, from about 35% toabout 60%, or from about 40% to about 60% by weight of the composition(microparticles and carrier).

C. Carrier Materials

In one embodiment, the microparticles are formed by adding a mixture ofthe drug and coating material(s) to a pharmaceutically acceptablecarrier. In one embodiment, the carrier is a hydrophilic or lipophiliccarrier. The resulting particles are suspended in the carrier. Thecarrier may be a single component or a mixture of components. Thecarrier can include solvents, surfactants, or other excipients. Thecarrier materials can alter or modify the rate of release of the drugfrom the microparticles and/or the rate of dissolution of the drug. Thecompositions may exhibit a biphasic release profile due to thecontrolled release properties of the microparticles and the controlledrelease properties of the carrier. Varying the qualitative andquantitative composition of the carrier materials may allow one tomodulate the release profile of the active agent. The carrier maycontain one or more rate controlling excipients which regulate releaseof the active agent. Exemplary rate controlling excipients include, butare not limited to, glyceryl behenate, GELUCIRE®, Cremophor,hydrogenated vegetable oil, bees wax, cellulosic polymers such ashypromellose, alginates, CARBOPOL® and combinations thereof.

In one embodiment, the carrier is a hydrophilic carrier containing asurfactant having a HLB value greater than about 10, greater than about12, greater than about 14, or greater than about 16, and/or is watersoluble. Exemplary hydrophilic carriers include, but are not limited to,polyethylene glycols, polyoxyethylene 32 lauric glycerides (availablefrom Abitech under the tradename ACCONON® M-44), polyoxyethylene 8caprylic/capric glycerides (available from Abitech under the tradenameACCONON® MC-8) and glycofurol. The hydrophilic vehicle can furthercontain one or more miscible solvents such as glycerin, ethanol,glycofurol, and caprylocaproyl macrogol-8 (available from GattefosseS.A., Saint Priest, France under the tradename LABRASOL®).

In one embodiment, the hydrophilic carrier is water or an alcohol. Inanother embodiment, the carrier is a hydrophilic carrier mixturecontaining polyethylene glycol, and optionally one or more surfactantsand/or water. In a particular embodiment, the hydrophilic carrier is amixture of PEG 400 (e.g., 57% by weight of the composition), water(e.g., 8% by weight of the composition), and Tween 20 (e.g., 10% byweight of the composition). The hydrophilic carrier can also containCremophor RH 40. The concentration of the hydrophilic carrier isgenerally from about 50% to about 85% by weight of the composition(microparticles and carrier), preferably from about 70 to about 80% byweight of the composition.

In another embodiment, the carrier is a lipophilic carrier. In apreferred embodiment, the lipophilic carrier has an HLB value of lessthan about 10 and/or is oil soluble. Exemplary lipophilic oily vehiclesinclude, but are not limited to, vegetable oils, medium chain mono-,di-, and triglycerides, glyceryl stearates (available from Sasol underthe tradename IMWITOR®), polyoxyethylated oleic glycerides (availablefrom Gattefosse, S.A., Saint Priest, France, under the trandenameLABRAFIL®), mineral oil, mono- and diglyceride emulsifiers such asglyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate,propylene glycol monocaprylate, and propylene glycol monolaurate(available from Abitec Corp., Columbus, Ohio, under the tradenameCAPMUL®), and dimethylpolysiloxanes such as simethicone.

The concentration of the lipophilic carrier is generally from about 10%to about 50% by weight of the composition (microparticles and carrier),preferably from about 5 to about 35% by weight of the composition.

D. Other Additives

The compositions described can contain one or more pharmaceuticallyacceptable excipients that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. Exemplary additives include, butare not limited to, solvents, suspending agents, dispersants, buffers,pH modifying agents, isotonicity modifying agents, preservatives,antimicrobial agents, and combinations thereof.

Suitable additives for inclusion in the compositions described hereininclude, but are not limited to, antioxidants (e.g., alpha tocopherols,such as vitamin E acetate, ascorbic acid, butylated hydroxyanisole, andbutylated hydroxytoluene); polar solvents (e.g., water, propyleneglycol, and glycerin); hydrophobic solvents (e.g., corn oil, castor oil,soybean oil, olive oil, fish oil, peanut oil, peppermint oil, saffloweroil, sesame oil, medium chain triglycerides, caprylic triglycerides,capric triglycerides derived from coconut oil or palm seed oil); andviscosity increasing agents (e.g., gelatin, glycerin, carrageenan,colloidal silicon dioxide, hydrogenated vegetable oil, povidone, andpropylene glycol alginate).

E. Dosage Forms

The microparticle compositions described herein are generally formulatedfor oral or parenteral administration. Suitable oral dosage foil asinclude capsules, such as hard or soft, gelatin or non-gelatin capsules,or oral suspensions or syrups. Suitable parenteral formulations includesuspensions.

1. Capsules

In one embodiment, the microparticle compositions (microparticlessuspended in a hydrophilic or lipophilic carrier) are encapsulated in acapsule, such as a hard or soft capsule. The capsules can be preparedfrom natural and/or synthetic film forming polymers. Suitable naturalfilm forming materials include, but are not limited to gelatin.Non-gelatin capsules include, but are not limited to, capsules made fromcarageenan, shellac, alginates, pectin, and zeins. Suitable syntheticfilm-forming polymers include, but are not limited to, methyl cellulose,hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and acrylates such aspoly (meth)acrylate.

The compositions can also be encapsulated in an enteric capsule, whereinthe capsule is coated with an enteric coating or the capsule shellcontains an enteric polymer as described in WO 2004/030658 to BannerPharmacaps, Inc.

Hard shell capsules are typically prepared by forming the two capsulehalves, filling one of the halves with the fill solution, and thensealing the capsule halves together to form the finished capsule. Softgelatin capsules are typically prepared using a rotary die encapsulationprocess. Such processes are known in the art.

The capsule shell can contain one or more additives. Suitable shelladditives include plasticizers, opacifiers, colorants, humectants,preservatives, flavorings, and buffering salts and acids, andcombinations thereof.

Plasticizers are chemical agents added to gelatin to make the materialsofter and more flexible. Suitable plasticizers include, but are notlimited to, glycerin, sorbitol solutions which are mixtures of sorbitoland sorbitan, and other polyhydric alcohols such as propylene glycol andmaltitol or combinations thereof.

Opacifiers are used to opacify the capsule shell when the encapsulatedactive agents are light sensitive. Suitable opacifiers include titaniumdioxide, zinc oxide, calcium carbonate and combinations thereof.

Colorants can be used to for marketing and productidentification/differentiation purposes. Suitable colorants includesynthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the softgel.Suitable humectants include glycerin and sorbitol, which are oftencomponents of the plasticizer composition. Due to the low water activityof dried, properly stored softgels, the greatest risk frommicroorganisms comes from molds and yeasts. For this reason,preservatives can be incorporated into the capsule shell. Suitablepreservatives include alkyl esters of p-hydroxy benzoic acid such asmethyl, ethyl, propyl, butyl and heptyl esters (collectively known as“parabens”) or combinations thereof.

Flavorings can be used to mask unpleasant odors and tastes of fillformulations. Suitable flavorings include synthetic and naturalflavorings. The use of flavorings can be problematic due to the presenceof aldehydes which can cross-link gelatin. As a result, buffering saltsand acids can be used in conjunction with flavorings that containaldehydes in order to inhibit cross-linking of the gelatin.

2. Oral Suspensions

Alternatively, the composition can be administered as an oralsuspension, such as a syrup. The solution or suspension may be preparedusing one or more pharmaceutically acceptable excipients. Suitableexcipients include, but are not limited to, surfactants, humectants,plasticizers, crystallization inhibitors, wetting agents, dispersingagents, pH adjusting agents, flavorants, colorants, and combinationsthereof.

III. Methods of Manufacture

A. Microparticles

The microparticles described herein may exhibit improved dissolution andenhance absorption in vivo as compared to formulations containing theactive agent suspended in an oil-based (e.g., lecithin and Capmul orpolyoxyl 40 stearate and glyceryl monostearate) or aqueous-basedcarrier. The microparticles can be made by a co-melting process orco-dissolving process. For example, the active agent can be melted,dissolved, or suspended in one or more molten fatty acids, conjugatedfatty acids, hydrophilic polymers, and/or surfactants at a temperaturedependent on the melting point of the active agent and any coatingmaterials used to form the microparticles. The active agent, coatingmaterial(s), and optionally any additives are melted at a temperaturetypically between about 40° C. and about 75° C., preferably betweenabout 40 and 60° C., in a suitable reactor vessel, such as a medicinetank. A solvent may be used to dissolve or suspend the active agent inthe coating material.

The active agent-coating material mixture is added to a lipophilic orhydrophilic carrier, typically at room temperature or less, withvigorous stirring and/or homogenization to form microparticles suspendedin the hydrophilic or lipophilic carrier. Alternatively, the hydrophilicor lipophilic carrier can be added to the mixture of drug and coatingmaterial(s) and homogenized to form microparticles.

The active agent-coating material mixture and the hydrophilic orlipophilic carrier are stirred for a period of time until the mixture ishomogeneous, typically for a period of time less than about 30 minutes,to form the microparticles. In one embodiment, the mixture is stirredfor about 10 minutes, preferably about 5 minutes to form microparticleshaving a diameter from about 100 nm to about 25 microns, preferablyabout 5 to about 25 microns, more preferably from about 10 to about 25microns, more preferably from about 10 to about 20 microns. In anotherembodiment, the microparticles have a diameter less than about 10microns, less than about 5 microns, less than about 1, less than 0.5microns, less than 0.25 microns, or less than 0.1 microns. The diameterof the microparticles can be varied by varying the mixing times;generally, the longer the mixing times, the smaller the particle size.

Homogenization processes can also be used to reduce the particle size.Homogenization is a fluid mechanical process that involves thesubdivision of particles or droplets into micron sizes to create astable dispersion or emulsion for further processing. This processoccurs when the fluid passes through a minute gap in the homogenizingvalve. This creates conditions of high turbulence and shear, combinedwith compression, acceleration, pressure drop, and impact, causing thedisintegration of particles and dispersion throughout the product. Afterhomogenization, the particles are of a uniform size, depending on theoperating pressure and the time of homogenization.

B. Encapsulation of the Microparticles

The microparticles, alone or suspended in the hydrophilic or lipophiliccarrier mixture, can be encapsulated in hard or soft capsules. Thecapsules can be gelatin capsules or non-gelatin capsules (e.g.,carageenan, starch, polysaccharides, etc.). Encapsulation can occur atroom temperature or at elevated temperatures (up to 35° C. for softgelatin capsules and up to 60° C. for non-animal soft shell capsules) tofacilitate the fill flow. Encapsulation in soft shell capsules may bedone using a rotary die encapsulation machine using standard procedures.The capsules are dried to the desired hardness and/or fill moisturecontent to facilitate the handling of the capsules during packaging,shipping, and storage. The fill weight range of the finished capsules istypically from 100 mg to 2200 mg in a capsule suitably sized forswallowing. The capsules are processed following standard procedures andcan be packaged in either bottles or blisters packs. The capsules may becoated with one or more delayed release, extended release, or entericmaterials. Alternatively, the microparticles can be incorporated into anenteric capsule, wherein the enteric polymer is contained in the capsuleshell, as described in WO 2004/030658 to Banner Pharmacaps, Inc.

IV. Methods of Use

The compositions described herein can be used to administer an activeagent to a patient in need thereof. The amount of active agent to beadministered can be readily determined by one of ordinary skill in theart and is dependent on several factors, including the disease ordisorder to be treated and the age and weight of the patient.Specifically, the compositions described herein can be used toadminister poorly insoluble and/or poorly absorbable active agents. Thecompositions described herein can enhance dissolution and/orbioavailability of the active agent.

The dissolution performance of the compositions described hereindepends, at least in part, on the HLB of the surfactant and/or modifiedfatty acid. Hydrophobic drugs of low aqueous solubility present poordissolution characteristics. To improve drug dissolution, the physicalcharacteristics of the drug can be modified to increase effectivesurface area. The use of high HLB surfactants as formulation adjuvantsmay improve the drug dissolution by enhancing wetting and micellarsolubilization in presence of water or polar solvents. Further,absorption of the active agent may be enhanced due to the fatty acidcoating on the microparticles.

Microparticles containing a water-insoluble drug coated with aconjugated fatty acid suspended in a hydrophilic carrier exhibit fasterdissolution rates than aqueous or oil-based suspensions of the drug. Forexample, in vitro release studies of formulations containing fattyacid-coated fenofibrate microparticles showed approximately 85%dissolution of fenofibrate in 15 minutes and approximately 100%dissolution in 60 minutes, which is significantly faster thanfenofibrate suspended in an aqueous carrier. Under fasting conditions,the fenofibrate concentration in vivo was more than twice theconcentration of fenofibrate suspended in water. Under non-fastingconditions, absorption of fenofibrate from fatty acid coated drugparticles was substantially higher than for fenofibrate suspended inwater. Fenofibrate absorption of fatty acid-coated microparticles wascomparable under non-fasting and high fat conditions.

In another embodiment, in vitro release studies of formulationscontaining cilostazol showed 100% dissolution of cilostazol in 15minutes, which is significantly faster than cilostazol suspended in anoil-based carrier containing lecithin and Capmul (CLZ-02) and cilostazolin tablet form suspended in water (Pletal®). The same formulation showedgreater absorption in vivo compared to the aqueous and oil-basedsuspensions under fed and fasting conditions. For example, thecompositions described herein exhibited an almost 400% increased in theAUC₀₋₂₄ under fasting condition compared to Pletal® and an almost 100%increase in the AUC₀₋₂₄ compared to cilostazol suspended in an oil-basedcarrier containing lecithin and Capmul.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

EXAMPLES Example 1 Preparation of Fatty Acid Coated FenofibrateParticles

Microparticles containing a fatty acid and fenofibrate were prepared.Glyceryl monostearate was melted at 70° C. with mixing. Fenofibrate wasadded slowly to the molten glyceryl monostearate with stirring. Themixture was maintained at 70° C. and the hydrophilic carrier was addedslowly with mixing at 350 rpm until the mixture was homogeneous. Themixture was cooled to 30° C. Following cooling, the mixture washomogenized until an aggregate-free suspension was obtained.

The composition of the drug and coating material mixture and thehydrophilic phase used to form the microparticles is shown in Table 1.Table 1. Composition of the drug and coating material mixture andhydrophilic phase

Drug and Coating Weight % of Material Mixture composition g/BatchPolyoxy 40 stearate or 10.5 10.5 Glyceryl monostearate Fenofibrate 14.514.5 Sub total 25.0 25.0 Hydrophilic phase % g/Batch PEG 400 57.0 57.0Water 8.0 8.0 Tween 20 10.0 10.0 Sub total 75.0 75.0 Total 100.0 100.0

Example 2 In Vitro Release Profiles of Fatty Acid Coated FenofibrateParticles

In vitro drug release studies were conducted using a USP dissolutionapparatus II (paddles) at 75 rpm. Experiments were conducted indissolution media at 37.0±0.5° C. in 1000 mL of 0.05 M sodium dodecylsulfate. Samples were withdrawn and analyzed via HPLC having at UVdetector. The detection wavelength was 286 nm. The results are shown inFIG. 1A. In vitro release studies of formulations containing fenofibrateshowed approximately 85% dissolution of fenofibrate in 15 minutes andapproximately 100% dissolution in 60 minutes, which is significantlyfaster than fenofibrate suspended in an oil-based carrier.

Example 3 Preparation of Fatty Acid Coated Cilostazol Particles

Particles containing cilostazol (14.5% by weight) were prepared usingthe procedure and materials described above. The microparticles wereformed by combining a mixture of glycerin ester of behenate (8.49% w/w),vitamin E acetate (8.49% w/w), sorbitan monostearate (Span 80, 1.00%w/w) and cilostazol with a hydrophilic carrier containing polyethyleneglycol (54.74% w/w), water (8.43% w/w), Cremophor RH 40 (1/89% w/w), andTween 20 (3.78% w/w). The mixture was homogenized using Ultra-Torraxfollowed by deaeration. The homogenized fatty acid suspension was passedthrough Ultra-Torrax three times to reduce the particle sizedistribution (<500 nm).

Example 4 In Vitro and In Vivo Release Profiles of Fatty Acid CoatedCilostazol Particles

In vitro drug release studies were conducted using a USP dissolutionapparatus II (paddles) at 75 rpm. Experiments were conducted indissolution media at 37.0±0.5° C. in 1000 mL of 0.05 M sodium dodecylsulfate. Samples were withdrawn and analyzed via HPLC having at UVdetector. The detection wavelength was 286 nm. The results are shown inFIG. 1B. In vitro release studies of formulations containing cilostazolshowed 100% dissolution of cilostazol in 15 minutes, which issignificantly faster than cilostazol suspended in an oil-based carriercontaining lecithin and Capmul (CLZ-02) and cilostazol in tablet formsuspended in water (Pletal®).

FIG. 2 shows the absorption of various cilostazol formulations under fedand fast conditions. FIG. 2A shows the enhanced absorption in vivo underfasting conditions for glycerin ester of behenate-coated cilostazolnanoparticles compared to Pletal® (cilostazol in tablet form, suspendedin water) and cilostazol suspended in an oil-based carrier containinglecithin and Capmul (CLZ-02). FIG. 2B shows the enhanced absorption invivo under fed conditions for glycerin ester of behenate-coatedcilostazol nanoparticles versus Pletal® (cilostazol in tablet form) andCLZ-02.

Example 5 In Vitro and In Vivo Release Profiles of Fatty Acid CoatedFenofibrate Particles

Fatty acid-coated particles of fenofibrate were prepared using aprocedure similar to the procedure described in Example 1. Thedrug-coating material mixture contained glyceryl ester of behenate(4.25% w/w), stearoyl macrogol glyceride (sold under the tradenameGelucire 50/13 and available from Gattefosee, 4.25% w/w), soybean oil(8.49% w/w), sorbitan monostearate (Span 80, 1.89% w/w), and fenofibrate(15.08% w/w). The fenofibrate was co-melted with the fatty acid mixtureand spread onto aluminum foil to allow it to cool. 33.96% of thefenofibrate/fatty acid mixture was added to a hydrophilic carriercontaining polyethylene glycol (54.74% w/w), water (7.54%, w/w),Cremophor RH 49 (1.89% w/w), and Tween 20 (1.89% w/w). The mixture washomogenized using Ultra-Torrax for five minutes followed by deaeration.The homogenized fatty acid suspension was passed through theUltra-Torrax three times to reduce the particle size distribution (<500nm).

A comparative study was conducted using two formulations: (1) afenofibrate suspension in aqueous solution and (2) fenofibrate/lipidparticles suspended in PEG 400. The in vivo absorption was in rats wasmeasured as described below.

Two formulations containing 20.0 mg fenofibrate/200 μL were administeredto two different group of rats (n=6) via oral gavage. For thenon-fasting experiments, each group of rats was given a normal diet adlibitum. For the fasting experiments, food was prohibited for 12 hoursprior to dosing and provided again 2 hours post-administration. Anothergroup was treated with a high fat meal containing 25% (W/W) peanutbutter. For all groups water was provided ad libitum. Blood samples werecollected at 0, 0.5, 1.0, 2.0, 3M, 4.0, 6.0, 8.0, 10.0, 12.0 and 24.0hours post administration and immediately centrifuged at 10,000 RPM for10 min to obtain plasma samples.

Plasma samples were vortexed with n-hexane/ethylacetate (90/10 v/v) andcentrifuged at 10,000 RPM for 4 min. The organic layer was separated anddried at 40° C. under vacuum overnight. The residue was reconstitutedwith acetonitrile and analyzed by HPLC. HPLC was done using a phenolcolumn (4.6×250 mm, 5 μM) at 25° C. using a UV detector (286 nm). Themobile phase was acetonitrile/0.02M phosphoric acid mixture. The resultsare shown in FIG. 3.

FIG. 3 is a graph showing the absorption of various fenofibrateformulations as a function of time. FIG. 3A is a graph showing thedifference in absorption of fenofibrate (fenofibric acid, ng/mL) as afunction of time (hours) for fatty acid-coated fenofibrate (∘) andfenofibrate suspended in water (Δ) under fasting conditions. Absorptionof fenofibrate in viva was improved more than two fold compared to thesuspension of fenofibrate in water.

FIG. 3B is a graph showing the difference in absorption of fenofibrate(fenofibric acid, ng/mL) as a function of time (hours) for fattyacid-coated fenofibrate (♦) and fenofibrate suspended in water (▴) undernon-fasting conditions and fatty acid-coated fenofibrate taken after ahigh fat meal (*). Absorption of fenofibrate from fatty acid coated drugparticles was substantially higher than for fenofibrate suspended inwater. Fenofibrate absorption of fatty acid-coated microparticles wascomparable under non-fasting and high fat conditions. T_(max) under highfat conditions was slightly longer than under non-fasting conditions.

FIG. 4 is a graph showing the food effect in rats on the absorption ofthree fenofibrate formulations: fatty acid coated fenofibrate particles(reference); solid lipid nanoparticles (SLN); and solid lipidnanoparticles with high fat, as a function of the formulation. The fattyacid-coated fenofibrate particles suspended in NaCl solution showed afood effect with normal diet: the high (158%) and low (142%) end ofAUC₀₋₂₄ were outside 80 to 125% of the equivalent range compared tofasting conditions. The fill formula containing solid lipidnanoparticles included the median (120%) and lower end (103%) of AUC₀₋₂₄within 80 to 125% of the equivalent range. Under high fat mealconditions (meal containing 25% (w/w) of peanut butter), the solid lipidnanoparticles formulation exhibited a more pronounced food effect thanunder normal diet (122% to 155% of the ratio of food effect by AUC₀₋₂₄).This observation suggests that 25% (w/w) of a high fat diet (e.g.,peanut butter) in normal rodent diet could enhance the absorption offenofibrate.

We claim:
 1. Microparticles comprising at least one water-insoluble active agent obtained by (a) dissolving, melting, or suspending at least one water-insoluble active agent in at least one fatty acid, conjugated fatty acid, or combinations thereof to form a mixture, and (b) mixing the mixture of step (a) with a liquid hydrophilic or lipophilic carrier to form the microparticles having a diameter from 100 nm to 25 microns, and wherein the microparticles and carrier are encapsulated in a soft or hard, gelatin, or non-gelatin capsule.
 2. The particles of claim 1, wherein step (a) further comprises at least one surfactant, hydrophilic polymer, or combinations thereof.
 3. The particles of claim 2, wherein the concentration of the surfactant is from about 1% to about 50% by weight of the microparticles.
 4. The particle of claim 2, wherein the concentration of the hydrophilic polymer is from about 1% to about 50% by weight of the microparticles, or if the hydrophilic polymer is polyethylene glycol, the concentration is from about 1% to about 80% by weight of the microparticles.
 5. The microparticles of claim 1, wherein the active agent has an enhanced rate of dissolution in aqueous media compared to a formulation containing the active agent suspended in aqueous media under fed or fasting conditions.
 6. The particles of claim 2, wherein the surfactant in step (a) has an HLB greater than about
 10. 7. The particles of claim 6, wherein the surfactant in step (a) has an HLB greater than about
 16. 8. The particles of claim 1, wherein the conjugated fatty acid is selected from the group consisting of C₁₀-C₁₈ monoglycerides, C₁₀-C₁₈ fatty acids conjugated to a polyalkylene oxide, C₁₀-C₁₈ fatty acids conjugated to a monosaccharide, and combinations thereof.
 9. The particles of claim 1, wherein the fatty acid is a C₁₀-C₁₈fatty acid.
 10. The particles of claim 9, wherein the fatty acid is selected from the group consisting of dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanoie (palmitic) acid, heptadecanoic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid, triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid, tritriacontanoic (ceromelissic) acid, tetratriacontanoic (geddic) acid, pentatriacontanoic (ceroplastic) acid, and combinations thereof.
 11. The particles of claim 2, wherein the hydrophilic polymer is selected from the group consisting of poloxomers, poloxamines, and polyethylene glycols.
 12. The particles of claim 1, wherein the water-insoluble active agent is selected from the group consisting of fenofibrate, cilostazol, acetazolamide, albendazole, allopurinol, azothioprine, carbamazepine, clofazimine, dapsone, diazepam, diloxanide furoate, doxycycline, efavirenz, furosemide, glibenclamide, griseofulvin, haloperidol, ibuprofen, lopinavir, nevirapine, niclosamide, nifedipine, paracetamol, parathyroid calcitonin, retinol palmitate, ritonavir, sulfadiazine, sulfamethoxazole, and sulfasalazine.
 13. The particles of claim 1, wherein the active agent is fenofibrate or cilostazol.
 14. The particles of claim 1, wherein the concentration of the fatty acid or conjugated fatty acid is from about 5% to about 15% by weight of the particles plus carrier.
 15. The particles of claim 2, wherein the concentration of the surfactant is from about 5% to about 15% by weight of the particles plus carrier.
 16. The particles of claim 2, wherein the concentration of the hydrophilic polymer is from about 5% to about 15% by weight of the microparticles and carrier.
 17. The particles of claim 11, wherein the concentration of polyethylene glycol is from about 30% to about 60% by weight of the microparticles and carrier.
 18. The particles of claim 11, wherein the concentration of polyethylene glycol is from about 40% to about 60% by weight of the microparticles and carrier.
 19. The particles of claim 1, wherein the hydrophilic or lipophilic carrier in step (b) is at or below room temperature.
 20. The particles of claim 1, wherein the particles have a diameter between 5 microns and 25 microns.
 21. The particles of claim 6, wherein the surfactant in step (a) has an HLB value greater than about
 14. 22. The particles of claim 2, comprising a surfactant and at least one fatty acid or conjugated fatty acid, hydrophilic polymer, or combinations thereof.
 23. The particles of claim 1, wherein when the active agent is fenofibrate, the percent dissolution of fenofibrate is about 85% after 30 minutes when conducted using a USP dissolution apparatus II (paddles) at 75 rpm in 1000 ml of 0.05 M sodium dodecyl sulfate at 37°±0.5° C.
 24. The particles of claim 23, wherein when the active agent is fenofibrate, the percent dissolution of fenofibrate is about 95% after 45 minutes.
 25. The particles of claim 23, wherein when the active agent is fenofibrate, the percent dissolution of fenofibrate is about 100% after 60 minutes. 